Guanylic acid derivatives and their use as drugs

ABSTRACT

Guanylic acid derivatives according to either of the formulae: ##STR1## in which Me is a metal trace element indispensable for the enzymatic activity of physiological processes. 
     These derivatives, prepared in gastro-resistant galenic form with in situ release of active ingredients, are proposed for the treatment of psychasthenia, depression, anxiety and geriatric disorders.

This is a 371 of PCT/FR95/00806 filed Jun. 16, 1995.

The present invention relates to guanylic acid derivatives and the useof these substances as drugs.

The molecule of 5'-guanylic acid and the processes for obtaining thismolecule have already been described in the literature. In particularreference is made to this product in the Merck Index, 11^(th) edition(Reference N° 4484). It is known that this molecule in the form of asodium salt may be used as a flavouring.

Also, this molecule has an important physiological role. Guanylic acidis a precursor of cyclic GMP which plays a known part inmicro-circulation.

A physiological balance exists both between adenosine and guanosine andbetween the two cations calcium and magnesium. The excess ofintracellular calcium and adenosine observed in elderly people leads toslowing of intellectual activity and asthenia. Magnesium and guanosineappear to have a reverse effect.

The therapeutic action, however, of the derivatives of guanylic acidhave not, to the knowledge of the applicant, ever been described.

There is however a considerable, increasing need for an effective drugwithout side effects to treat biological disorders related to ageing.

The applicant has set out to research molecules that meet this need, andhas thus been able to show that derivatives of guanylic acid can beused, among other uses, to treat these disorders and that they are nontoxic.

The present invention relates to derivatives of guanylic acid accordingto either of the general formulae (I) and (II) in which Me is a metaltrace element involved in the enzymatic activity of physiologicalprocesses, such as calcium (Ca), magnesium (Mg), copper (Cu), cobalt(Co), nickel (Ni), zinc (Zn), iron (Fe), selenium (Se), lithium (l),manganese (Mn) or any other monovalent or divalent cation chelated byguanylic acid: ##STR2##

It will be noted that in formula II the two metal substituants on thederivative may be different.

These derivatives are advantageously in the form of a microcrystallinepowder that is insoluble in water. They may be used alone or inassociation in formulations or compositions suitable for therapeuticuse.

Such compositions are preferably gastro-resistant in order to preventhydrochloric acidity of the stomach acting on the derivatives of theinvention. Such compositions may be those which comply with thestandards of the French Pharmacopeia.

The derivatives may be in the form of racemic mixtures or in the form ofstereo-isomers.

The present invention also relates to the hydrated forms of theabove-described derivatives, in particular those in which 6 to 8 watermolecules are complexed.

As a general rule, in particular at neutral pH, the derivatives of theinvention are in the form of non-ionized complexes. At acid pH suchcomplexes are likely to break up and form ionized derivatives.

The derivatives of the present invention may be prepared by solubilizingguanylic acid in a nonpolar organic solvent and adding the cation in theform of a chloride. The reaction is stoichiometric with a yield in theregion of 100%. A change in colour indicates the formation of thederivatives. After eliminating the solvents, the microcrystallinepowders are washed in water to eliminate the traces of cation which areunreacted. After drying, the powder has a microcrystalline form and isinsoluble in water and polar solvents. The melting point of allcompounds is in the region of 300° C. The NMR spectrum, centesimalanalysis and a single spot in thin layer chromatography confirm thestructure and the purity of the derivatives obtained. Spectral X-rayanalysis demonstrates that these derivatives are chelates.

The invention also relates to pharmaceutical compositions comprising atleast one derivative such as described above, in conjunction with one ormore diluent carriers, either excipients or additives that arecompatible and pharmaceutically acceptable.

The pharmaceutical compositions of the invention are preferably in anappropriate form for administration through oral, parenteral orintravenous route.

Advantageously the pharmaceutical compositions of the invention containa quantity of derivative as described above, adapted to a daily dosagein man of between approximately 0.2 g and approximately 3 g in one orseveral doses.

The invention relates more particularly to a composition or medicinalproduct containing a derivative such as described above and the use ofsuch derivative in order to obtain medicinal products intended to treat:

cerebral asthenia, by stimulating cognitive functions such as thememory,

psychasthenia, depression in mild and serious forms, anxiety,

cation deficiency, such as those complexed in the compounds of theinvention,

vascular disorders relating to macro or micro circulation such asvasodilatation.

The derivatives that are the subject of this invention demonstrate inparticular an anti-radical, healing, vasodilator effect.

In comparison with the molecules already used to treat the illnesses anddisorders indicated above, the derivatives of the present invention havenumerous advantages. In particular they are non toxic and have easy cellpenetration properties. Moreover, they help cation entry into thesecells via the specific channels.

The invention is illustrated by the following, non-limiting, examples:

EXAMPLE 1 Preparation of calcium 5'-guanylate or 5'-guanylicate

    ______________________________________                                         ##STR3##                                                                     Molecular weight:    401 (anhydrous)                                          Centesimal composition:                                                       C %                  29.95                                                    H %                   3.02                                                    N %                  17.47                                                    Ca %                 10.04                                                    ______________________________________                                    

Procedure

0.002 mole of 0.85 g of disodium 5'-guanylate (or 5'-guanylicate)(marketed by Fluka under reference 51090) are dissolved (warmingslightly) in 10 ml of distilled water. 0.0025 mole of 95% calciumchloride or 0.25 g are dissolved separately in 10 ml of water. Undervigorous stirring the calcium solution is added to the sodium solution.A colourless precipitate is immediately formed and stirring iscontinued.

After dewatering the precipitate is washed with distilled water toeliminate the residual sodium chloride.

Recrystallisation is carried out in absolute ethanol (which does notdissolve the residual sodium chloride).

EXAMPLE 2 Preparation of magnesium 5'guanylate or 5'-granylicate

    ______________________________________                                        Molecular formula:                                                                             C.sub.10 H.sub.12 N.sub.5 O.sub.8 P.Mg (with n H.sub.2                        0)                                                           Molecular weight:                                                                              385 (anhydrous)                                              Centesimal composition:                                                       C %              31.19                                                        H %               3.14                                                        N %              18.19                                                        Mg %              6.32                                                        ______________________________________                                    

EXAMPLE 3 Preparation of manganese 5'guanylate or 5'-guanylicate

    ______________________________________                                        Molecular formula:                                                                             C.sub.10 H.sub.12 N.sub.5 O.sub.8 P.Mn (with n H.sub.2                        0)                                                           Molecular weight:                                                                              415.93 or 416 (anhydrous)                                    Centesimal composition:                                                       C %              28.85                                                        H %               2.91                                                        N %              16.84                                                        Mn %             13.24                                                        ______________________________________                                    

EXAMPLE 4 Preparation of copper (cuprous) 5'-guanylate or 5'-guanylicate

    ______________________________________                                        Molecular formula:                                                                             C.sub.10 H.sub.12 N.sub.5 O.sub.8 P.Cu (with n H.sub.2                        0)                                                           Molecular weight:                                                                              424.50 (anhydrous)                                           Centesimal composition:                                                       C %              28.29                                                        H %               2.85                                                        N %              16.50                                                        Cu %             14.97                                                        ______________________________________                                    

EXAMPLE 5 Preparation of iron (ferrous) 5'-guanylate or 5'-guanylicate

    ______________________________________                                        Molecular formula:                                                                             C.sub.10 H.sub.12 N.sub.5 O.sub.8 P.Fe (with n-H.sub.2                        0)                                                           Molecular weight:                                                                              416.85 (anhydrous)                                           Centesimal composition:                                                       C %              28.82                                                        H %               2.90                                                        N %              16.80                                                        Fe %             13.48                                                        ______________________________________                                    

EXAMPLE 6 Preparation of lithium 5'-guanylate or 5'-guanylicate

    ______________________________________                                        Molecular formula:                                                                             C.sub.10 H.sub.12 N.sub.5 O.sub.8 F.Li.sub.2 (with n                          H.sub.2 O)                                                   Molecular weight:                                                                              375 (anhydrous)                                              Structural formula:                                                                             ##STR4##                                                    Centesimal composition:                                                       C %              32.03                                                        H %               3.23                                                        N %              18.68                                                        Li %              3.70                                                        ______________________________________                                    

EXAMPLE 7 Activity of the manganese derivative of guanylic acid

To demonstrate the advantage of this product, synthesised in example 2,various studies have been conducted in animal and man.

1) Animal studies

In respect of acute toxicity, the LD 50 by oral route in mice and ratswas found to be higher than 5 g/kg. This toxicity is therefore very low.With repeated administrations for two weeks in rats at a dose of 1g/kg/d no change in behavioural and biological parameters was observed.

From a pharmacological viewpoint, anti-asthenia activity was evidencedin rats kept under normobar hypoxia as described by Prioux-Guyonneau etal. (J. Physiol, 1976, 72, 579-587). This hypoxia leads to reducedmotility and exploratory activity which is restored by a singleadministration of 0.1 g/kg of the test derivative one hour before thetest.

Partial magnesium deficiency (40 ppm/d) induced as described by Durlachet al. (In Magnesium Deficiency: Physiopathology and TreatmentImplications, Edit. Halpern, Durlach and Kargeras 1984) causesbehavioural disorders, in particular reduced learning capacity seenduring sound avoidance behaviour (Pole Climbing Test). A two-weektreatment by oral route with the derivative at a dose of 100 mg/kg/dovercomes the effects of this deficiency on behavioural disorders.

2. Studies in man

A clinical study, conducted in five patients aged over 70 years whocomplained of memory disorders together with considerable intellectualfatigue, which used a daily dose of 300 mg of the derivative in the formof gastro-resistant film-coated tablets, showed an improvement invarious symptoms and recovery of normal cognitive activity in thesepatients.

No side effect was observed in these patients.

We claim:
 1. Guanylic acid derivatives according to either of thefollowing general formulae (I) and (II): ##STR5## in which Me is a metaltrace element involved in the enzymatic activity of physiologicalprocesses.
 2. The derivatives in accordance with claim 1, characterizedin that Me is a metal able to form a monovalent or divalent cation. 3.The derivatives in accordance with claim 1, characterized in that Me isMg, Cu, Ca, Co, Zn, Ni, Se, Mn, Li or Fe.
 4. The derivatives inaccordance with claim 1, characterized in that they are in the form ofracemic mixtures or in the form of stereoisomers.
 5. A drug containingat least one of the compounds in accordance with claim
 1. 6. The drug inaccordance with claim 5, characterized in that it comprises a quantityof active derivative that is adapted to a daily dosage in man of between0.2 and 3 g.
 7. A pharmaceutical composition containing an effectivequantity of at least one derivative of claim 1, in association with oneor more diluents, excipients or additives that are compatible andpharmaceutically acceptable.
 8. The pharmaceutical composition inaccordance with claim 8 prepared for oral, parenteral or intravenousadministration.
 9. A method of treating psychasthenia, depression,anxiety, cerebral asthenia, vascular illnesses or cation deficiencies,comprising administering the guanylic acid derivative of claim 1 to apatient in need thereof.
 10. A method of treating psychasthenia ordepression comprising:administering the guanylic acid derivative ofclaim 1 to a patient in need thereof.